Thioether ethers



United States Patent 3,384,670 THIOETHER ETHERS Walter Reifschneider,Midland, Mich., assignor to The Dow Chemical Company, Midland, Mich., acorporation of Delaware No Drawing. Continuation-impart of applicationsSer. No. 205,503, June 27, 1962, and Ser. No. 359,763, Apr. 14, 1964,which latter application is a continuation-in-part of application Ser.No. 205,512, June 27, 1962. This application Oct. 6, 1966, Ser. No.584,691 9 Claims. (Cl. 260-609) ABSTRACT OF THE DISCLOSURE Compounds ofthe formula M GOQH.

wherein R and G independently represent alkyl from 2 to 12, inclusive,carbon atoms, cyclopentyl or cyclohexyl; and n is 1 to 4, and m is 0 to4; useful as pesticides, intermediates in the preparation of dyestuffsand oil additives.

This application is a continuation-impart of application Ser. No.205,503, filed June 27, 1962, and of application Ser. No. 359,763 filedApr. 14, 1964, which latter application is a continuation-in-part ofapplication Ser. No. 205,512, filed June 27, 1962, now abandoned.

The present invention is directed to thioesters and in particular isdirected to novel thioethers corresponding to the formula In the presentspecification and claims, R represents a member of the group consistingof alkyl containing from 2 to 12, inclusive, carbon atoms, cycloalkyl,phenyl, substituted phenyl whereof the substituents are selected fromnitro, lower alkyl, and phenoxy; G is independently of the same scope asR, the subscript n represents an integer from 1 to 4, and the subscriptm represents an integer from 0 to 4; and when m is zero and R is phenylit is substituted phenyl of which the substituents are nitro or phenoxy.

Thus the present compounds are either, when m represents 0, of the firstsub type gogam.

or, when m represents 1 or more, of the second sub type which can berepresented as equivalent to wherein R and n have the values previouslyset forth.

The novel compounds are colorless to yellow crystalline solids or oils.They are slightly soluble in water but readily soluble in various commonorganic solvents such as lower alkanols, benzene and the like. Thecompounds are useful as insecticides, molluscacides, and herbicides; asinhibitors of the germination of fungus spores, they are effectivefungistats. The compounds are also useful as 3,384,670 Patented May 21,1968 additives to improve the properties of lubricating oils especiallydesigned for operation under high pressures and temperatures; they areuseful as intermediates in the preparation of dyestuffs and biologicallyactive materials; they are also of value as solvent additives in themodification of behavior of mixed solvent systems. They are useful asinhibitors of the germination of seeds of the Brassicacea. Various ofthe compounds are coccidiostats.

The compounds are prepared by a process which comprises the steps ofcausing a reaction between a molecular proportion of an aromatic etherhalide compound corresponding to the formula Yin 0 X5 and m molecularproportions of a first mercaptan corresponding to the formula and nmolecular proportions of a second mercaptan corresponding to the formulawherein X and Y are halogens, Y being of greater molecular weight thanX, when R and G are not identical; R, G, m and n, have the valuespreviously stated, and Q represents hydrogen, alkali metal, or cuprouscopper. During the reaction to prepare the present compounds, mmolecules of first type mercaptan react first at the site or sites ofthe halogen Y, and thereafter n molecules of the second type mercaptanreact at the site or sites of the halogen X, with each molecule ofaromatic halide. Small amounts of mercaptan maybe lost in sidereactions. Thus, when it is desired to prepare the present compound in ahigh state of purity and with a minimum of necessary postsynthesispurification procedure, the starting reactants should be employed inequimolecular proportions, or preferably, with any mercaptan in Slightexcess. However, other proportions may be employed if desired, andunconsumed starting material of whatever identity may, if desired, berecycled into further synthesis process.

The reaction goes forward at temperatures over a wide range, such asfrom 30 to 350 C., but initiates most readily when heated to atemperature somewhat higher than room temperature. A preferredtemperature range is from to 230 C. Under these conditions the reactionis, in general, exothermic and goes forward to completion with goodyield calculated upon the basis of consume-d starting material. When Qis hydrogen, hydrogen halide of reaction is evolved and means for itsorderly disposal are advantageously provided.

Typically, in the preparation of the com-pounds of the presentinvention, reaction between the mercaptan starting material and thearomatic ether halide starting material will initiate and go forwardonly when there is employed, a catalytic amount of both a source ofcuprous ion and of a nitrogenous base. Thus, in the preparation of many,and probably all of the present compounds, the employment of suchcatalyst is essential and critical, although the exact weight is notcritical. Certainly the employment of such catalyst is in all caseshighly advantageous. The source of cuprous ion may be metallic copper,in which case the copper reacts in some way to obtain cuprous halide.Also, cuprous oxide may be employed as a source of cuprous ion in whichcase water of reaction is evolved and cuprous halide results. Cuprouschloride itself or other cuprous salt may be employed. The employedweight is not critical, but may vary from a very small trace amount,less than V of 1 molar percent, to as much as an amount equimolecularwith either reactant or even greater. In general, the employment oflarger amounts is accompanied by no major advantage and, beingexpensive, is not preferred.

The nitrogeneous base may be ammonia, a primary, secondary, or tertiaryaliphatic or aromatic amine or a nitrogenous heterocycle wherein thenitrogen acts, or is capable of acting, as a basic substance. Ifdesired, the nitrogenous base may be a naturally liquid substance whichis employed as a reaction medium. Otherwise, such base is dissolved ininert liquid reaction medium such as an aromatic or aliphtic hydrocarbonoil.

It is preferred, in at least laboratory quantities, to employ thenitrogeneous base catalyst substance in sufficient excess that portionsof it may also act as hydrogen halide acceptor and yet further portionsmay continue to function, unreacted, in the necessary catalytic manner.

In carrying out the reaction to prepare the compounds of the presentinvention, the aromatic halide and the first mercaptan, when m isgreater than zero are intimately mixed and blended, in any order and indesired amounts, with source of cuprous ion and nitrogeneous base ashereinbefore described, preferably in liquid reaction medium which maybe inert reaction medium or preferably nitrogenous base catalyticreaction medium and thereafter heated, to a temperature at whichreaction takes place promptly. In one convenient method of practicingthe present method, the reaction temperature may be the refluxtemperature of the liquid reaction medium. In this situation, heatingmay be continued at the boiling temperature of the reaction mixture andunder reflux for a period of time to carry the first step reaction tocompletion. When second mercaptan unlike the first is employed, it isthen added to the mixture resulting from first step reaction, andessentially the same procedures are repeated.

Upon completion of the reaction, the desired compounds of the presentinvention are separated in manners which, in view of the teaching of theinstant specification, will be evident to skilled chemists. In one suchmanner, the reaction mixture, hot from heating to the reactiontemperature, is poured into a mixture of ice and concentratedhydrochloric acid whereupon a precipitate forms from which the desiredproduct can be extracted as a solvent-soluble fraction. Representativeextraction solvents include diethyl ether, chlorinated hydrocarbons, andbenzene. In any event the reaction product is extracted with solvent,the solvent extract dried over an inert drying agent such as, forexample, anhydrous potassium sulfate or the like; the solvent vaporizedand removed and the remaining product chilled or otherwise induced tocrystallize and, if desired, recrystallized from a solvent such as alower alkanol.

When production of the present compounds is to be carried out on anindustrial scale, various other methods of separation and purificationmay be preferred, including, for example, centrifugation, decantation,vacuum distillation, and the like.

The following examples, without more, will enable those skilled in theart to practice the present invention.

Example 1.Phenyl p-(hexylthio)phenyl ether In the instant example,having reference to the generic formula of the present compounds, Inbecomes zero, It becomes 1, and R is normal hexyl.

A reaction mixture is prepared, consisting of 373.6 grams (1.5 moles) ofp-bromophenyl phenyl ether, 30 grams of ouprous bromide, and 265 grams(approximately 2.3 moles) of sodium n-hexylmercaptide dispersed in oneliter technical grade 2,4-lutidine. The resulting reaction mixture isplaced in a flask under reflux. In this situation, the reaction mixtureis heated at its reflux temperature (a pot temperature betweenapproximately 150 and 175 C.) for 30 hours, with stirring, to carry thereaction to completion. At the end of this reaction period, theresulting hot mixture is poured into a mixture of shaved ice and excessconcentrated hydrochloric acid. As a result of these procedures, the icemelts and basic substances react with hydrochloric acid; in theresulting acidified water a precipitate forms. The precipitate iscollected by filtration and is extracted with ether, the ether extractliquid being saved. This liquid is dried over a bed of anhydrouspotassium carbonate which also neutralizes remaining traces of acidicsubstances; the resulting liquid is warmed tovaporize and remove ethersolvent and obtain a residual oil. This oil is fractionally distilled atgradually rising temperatures and declining subatmospheric pressure, toobtain a colorless, oily phenyl p-(n-hexylthio)phenyl ether product ofmolecular weight approximately 285, as determined by mass spectrumanalysis.

The compound of the present example is useful as an insecticide for thecontrol of domestic insects. The application of 500' parts of the saidcompound as sole toxicant, per million parts of resulting aqueousdispersion to water continuing a heavy population of aquatic larva-e ofmosquitos results in a complete kill of the insect larvae.

Example II.Bis( (p-phenylthio) phenyl)ether In this example, m. isunity, G is phenyl, n is unity, and R is phenyl, in the generic formulaExample III.Bis (m-phenoxyphenyl) sulfide In the generic formula of thepresent invention, as here applied, m is zero, It is unity, R issubstituted phenyl of which the substituent is phenoxy.

In procedures essentially similar to the foregoing, there is caused areaction between m-bromophenyl phenyl ether and m-phenoxybenzenethiolthere is obtained a bis(mphenoxyphenyDsulfide product as a yellow oilboiling at 231-235 C. under 0.3 millimeter mercury pressure, absolute.The compound has a refractive index n/ D of 1.6490 for the D line ofsodium light at 25 C. It is highly selectively toxic to Limnaiud snails(for example Planorbis spp.) which are alternate hosts of various humanand animal parasites such as liver flukes and schistosomiasis. Atheavier rates the compound is a herbicide.

Example IV .3- (cyclohexylthio 5 -cyclopentylthio phenyl3,5-bis(dodecylthio) phenyl ether In the instant example, under thegeneric formula, each of m and n is two; one embodiment of G iscyclohexyl and one is cyclopentyl; each embodiment of R is dodecyl.

The present synthesis takes advantage of the fact that the reactivity ofa halogen substituent upon an aromatic nucleus in the preparation of thepresent products, follows the order of the molecular weight. Because ofthis, a compound of the present invention may have more than one kind ofradical represented by either of G and R in the generic disclosurehereinbefore.

In a mixture of 250 milliliters technical 2,4-lutidine, 150 millilitersquinoline and 20 grams cuprous oxide as mixed liquid reaction medium, isdispersed 46.5 grams (0.1 mole) 3-bromo-5-chlorophenyl 3,5-diiodophenylether and 40.4 grams (0.2 mole) of dodecyl mercaptan. The resultingreaction mixture is heated, with stirring at its boiling temperature andunder water-trapped reflux for 2 hours. Thereafter, there is added 10.2grams (0.1 mole) of cyclopentane thiol, as heating and stirring arecontinued for 2 hours further. At the conclusion of the reaction time,there is added 11.6 grams (0.1 mole) cyclohexanethiol and reactionconditions are maintained for two hours further. Thereafter, theresulting hot mixture is poured directly into a mixture of chipped iceand 500 milliliters concentrated hydrochloric acid. As a result of theseprocedures, the ice melts and a solid separates in the resulting aqueousdispersion. This solid is collected by filtration and an acetone extractmade of it. The acetone extract is washed twice with hydrochloric acidand then dried over anhydrous potassium carbonate. From the resultingdry acetone solution, acetone solvent is evaporated, leaving anoff-white product solid which is recrystallized from chloroform toobtain off-white crystals of 3(cyclohexylthio)-(5-cyclopentylthio)phenyl 3,5-bis- (dodecylthio)phenylether having the structure formula l S r H (emu-cm and having molecularweight of 769.4.

By employing the different reactivities of the different halogensubstituents upon aromatic nuclei, and by using therewith predeterminedmolar amounts of reactants, it is possible to direct a predterminedmercaptan of thiol substituent to any predetermined ring carbon atom ofthe diphenyl ether nucleus. It is desired to use any mercaptan reactantin an amount slightly less than that stoichiometric with the halogenatedsite of sites upon which it is desired to attach a -thio radical.

Example V.o-(Cyclopentylthio)phenyl phenyl ether Applying the genericformula to the persent example, In becomes zero, n is unity and 'R iscyclopentyl.

A reaction mixture is prepared consisting essentially of 24.2 grams (0.1mole) of o-bromophenyl phenyl ether, 10.2 grams (0.1 mole) ofcyclopentane thiol, and grams cuprous bromide dispersed together in 200milliliters mixed technical xylidines as hydrogen halide acceptor,catalyst, and liquid reaction medium. The resulting reaction mixture isheated for approximately 3 hours at its boiling temperature and underreflux and with stirring, to carry the reaction to completion. At theconclusion of the reaction time, the resulting hot mixture is poureddirectly into a mixture of chipped ice together with 250 millilitersconcentrated hydrochloric acid. As a result of these procedures, the icemelts and a dark solid separates in the resulting aqueous dispersion.This solid is collected by filtration and a benzene extract thereofprepared; the extract is washed twice with 10 percent hydrochloric acidand dried over potassium carbonate. From the resulting dry benzenesolution, benzene solvent is heated and vaporized to obtain a colorlessoil which is redistilled to obtain an oily o-(cyclopentylthio)phenylether which is liquid at room temperature and has a molecular weight ofapproximately 270.4. In the pure form, the product boils at 141 C. underpressure of 0.2-0.3 millimeters mercury absolute, and has a refractiveindex n/D of 1.6062 at 20 C.

In procedures essentially the same as the foregoing, by the use ofappropriate starting materials, other products of the present inventionare prepared as follows:

From m-iodophenyl phenyl ether and m-nitrobenzenethilol, am-(m-nitrophenylthio)phenyl phenyl ether product.

Example VI.o-(Hexylthio)phenyl phenyl ether Under the generic formula,in this example, mbecomes zero, n becomes 1, and R is hexyl.

In procedures essentially similar to the foregoing except thato-bromophenyl phenyl ether is employed in the reaction mixture insteadof the p-analogue, there is prepared, in good yield, o-(hexylthio)phenylphenyl ether as white crystals readily soluble in various common organicsolvents. Elemental analysis and infrared spectrum confirm the assignedstructure.

In procedures essentially the same as the foregoing, by the use ofappropriate starting materials, other products of the present inventionare prepared as follows:

From p-bromophenyl phenyl ether and sodium t.-butylmercaptide, ap-(t.-butylthio)phenyl phenyl ether product as white crystals.'Itsbiological properties are closely similar to those foregoing.

Also, employ the sodium salt of n-butylmercaptan in procedures otherwiselike the foregoing, there is obtained a p-(butylthio)phenyl phenyl etherproduct.

From o-chlorophenyl phenyl ether and sodium ethyl me-rcaptide, ano-(ethylthio)phenyl phenyl ether product as off-white crystals meltingat 53 53.5 C. This product is ascaricidal, herbicidal, and useful forthe control of certain molluso vectors of Schistosomiasis.

Under the generic formula, m is zero, n is unity, and R is ethyl.

From p-iodophenyl phenyl ether and sodium ethyl lnercaptide, ap-(ethylthio)phenyl phenyl ether product as a colorless oil having arefractive index n/ D at 25 C. of 1.6027 and boiling at 1l5-118 C.,under pressure of 0.1 millimeter mercury absolute. This product hasselective herbicidal properties.

The general formula applies alike to the foregoing and to the presentpreparation; the site of the group {SR) differs.

From m-bromophenyl phenyl ether and sodium ethyl mercaptide, acolorless, oily m-(ethylthio)phenyl phenyl ether having a refractiveindex n/D of 1.6002 at 25 C., and boiling at 124-126 C. under pressureof 0.8 millimeter mercury, absolute. The compound is coccidiostatic, andis an effective herbicide.

The generic formula is applied to the present embodiment of theinvention as to the foregoing.

From p-bromophenyl phenyl ether and isopropylmercaptan, a colorless,oily p-(isopropylthio)phenyl phenyl ether product boiling at l36 C.under pressure of 0.4-0.5 millimeter mercury, absolute, and having arefractive index n/ D of 1.5873 at 25 C. The compounds harmlessly ridmice of tapeworms and trichostrongylid worms; it is a molluscacide andat 1 part per million in water kills all of a heavy population ofDaphnia (water fleas). It is also herbicidal.

In the present embodiment, m is zero, n is unity, and R isopropyl in thegeneric formula.

Despite the adverse experience reported by Brewster and Stevenson(Journal of the American Chemical Society, Volume 62, pages 3144-3146)good results have been obtained by the direct halogenation of diphenylether in the absence of catalyst and solvent, in preparation of variousof the halogenated diphenyl ethers used as starting materials herein.The isomeric preferences mentioned by Brewster and Stevenson appear tobe shown by the products of such halogenation and resolution into pureproducts of the resulting sometimes isomeric mixtures has not beendifiicult.

The authority cited, supra, shows various methods of preparation andcontains references to other.

When it is desired to prepare a pure halogenated diphenyl ether compoundof a precise isomeric structure, the method of Ullman and Sponagel isavailable and by the employment of the appropriately substituted phenolsand benzenes leads easily to the desired halogenated diphenyl ethers.The method is set forth in Liebigs Annallen der Chemie, Band 350, pages83-107. The method has been extended beyond even their original scope bynumerous authorities.

The necessary mercaptans and thiols are either articles of commerce orare readily prepared in such known methods as are used in routineproduction, by the employment of suitable starting materials. Suchmethods are set forth in Volume 1 of Organic Chemistry of BivalentSulfur (Chemical Publishing Company, New York, 1958) by Reid.

I claim:

1. Compound corresponding to the formula (mango-Q (s41).

wherein R represents a member of the group consisting of alkylcontaining from 2 to 12, inclusive, carbon atoms, and

cyclopentyl, cyclohexyl; and G is independently of the same scope as R,the subscript n represents an integer from 1 to 4, and the subscript mrepresents an integer from 0 to 4.

2. Bis(m-phenoxyphenyl)sulfide.

3. 3-(cyclohexylthio) (5 cyclopentylthio)phenyl 3,5- bis (dodecylthio)phenyl ether.

4. o-(Cyclopentylthio) phenyl phenyl ether.

. o-(Ethylthio)phenyl phenyl ether. p-(Ethylthio)phenyl phenyl ether.M(Ethylthio)phenyl phenyl ether. p-(Isopropylthio)phenyl phenyl ether.p-(n-Hexylthio)phenyl phenyl ether.

References Cited Marziano et 211., La Riceria Scientific'a, 31 II-A.,pp. 88-89 (1961).

Arcoria et al., Gazz. Chim. Ital., vol. 91, pp. 228-229.

Arcoria et 211., La Riceria Scientifica, 28, No. 9, pp. 1842-46 (1958).

Blake et al., High Temperature Hydrolic Acids, Defense DocumentationCenter for Scientific and Technical Information, WADC Technical Report54-532, Part III, Astia Document No. AD118170, p. 10 (April 1957).

CHARLES B. PARK-ER, Primary Examiner.

D. R. PHILLIPS, Assistant Examiner.

